The focus of this Perinatal Emphasis Research Center is Metabolic Regulation of Fetal Growth. The purpose of this research focus is to perform experiments in comparative reproductive and developmental physiology and cell biology to determine causes of intrauterine fetal growth retardation (IUGR) and metabolic consequences in the fetus. Studies will be conducted in animals (pregnant sheep and their fetuses) and pregnant women. These studies will address the following experimental aims and hypotheses: (I) in pregnant sheep, deprivation of glucose supply from the mother to the fetus and fetal insulin deficiency result in IUGR, placental and fetal metabolic adaptations that support placental and fetal viability by decreasing fetal growth and reducing the drain on maternal nutrients, and changes in fetal protein and energy metabolism that have systemic, cellular, and molecular components that operate to maintain energy metabolism at the expense of growth; (II) in pregnant sheep IUGR can develop spontaneously secondary to measurable changes in placental blood flow, structural growth, and function that produce sever fetal growth retardation with unique metabolic disturbances; (III) in pregnant women, pregnancies complicated by IUGR have measurable changes in amino acid metabolism and transport by the placenta, and imbalances in the supply and utilization of glucose, that can be defined using stable isotopic amino acid and glucose tracers and glucose clamp experiments, and are direct correlates of the mechanisms leading to IUGR in the two animal models. The animal studies are supported by the UCHSC Perinatal Research Facility which includes a hyperthermia chamber and the laboratory equipment and staff to conduct all physiologic and biochemical measurements proposed. There will be collaborative work also in special surgical procedures, cell physiology and biochemistry techniques, and molecular chemistry procedures. A specific addition to the Center, based on the successful models of IUGR, is the inclusion of new investigators and collaborators with research, and especially training capacities. Clinical studies are conducted at the University of Milano, Milano, Italy. The Center is supported by an Administrative Core that includes Internal and External Advisory Committees and an annual Research Review Meeting, a newly organized to provide more efficient and productive operation and new laboratory and statistical scientific advances as well. Understanding the causes and consequences of IUGR through the integration of the basic and clinical research in this Center should lead to rational preventive and therapeutic measures to diminish the incidence and severity of IUGR and thus to improve fetal and neonatal survival and health.